Nor-UDCA and Bis-Nor-UDCA are ursodeoxycholic acid analogs with modified physiochemical properties, like solubility, critically micellar concentration, or hydrophilicity (Roda et al., Dig Dis and Sciences, 1989). A method for the synthesis of 24-nor-5β-cholan-23-oic acid was already described by Schteingart and Hofmann (Journal of Lipid Research, 1988). In vitro experiments demonstrated their efficacy in animal models of cholestatic liver disease (PCT/EP2005/052178). A method for the preparation of Nor-UDCA is described in EP 0624595 B1. However, this document is silent with respect to characteristic chemical and physical properties, purity, extent of crystallization and the particle size of the synthesized Nor-UDCA.
The application of bile acids, especially ursodeoxycholic acid, in the treatment of cholestatic liver diseases, like Primary Biliary Cirrhosis, is well known and published already in the eighties of the last century (Poupon et al., Lancet, 1987). While the use of current available pharmaceutical preparations only results in the successful treatment of a subset of patients, there is a need for patients who do not respond the ursodeoxycholic acid therapy or suffer from cholestatic liver diseases or metabolic diseases that are not treatable with ursodeoxycholic acid.
Depending on the pH-value of the solvent bile acids are of low solubility. An adequately good solubility of bile acids in the intestinal tract is a prerequisite for a successful pharmaceutical treatment. Solubility may be improved by salt formation of Nor-UDCA.
A second objective is a preparation with a sufficient oral bioavailability. A high in vitro-dissolution rate is a prerequisite for sufficient oral bioavailability. Micronization, e.g. the production of a pharmaceutical preparation with a very small defined particle size (>60% with a diameter of less than 10 μm), is an established method to increase the dissolution rate. A known, but elaborate process to achieve micronized particles is by extensive milling.
An additional objective of the present invention was to provide a physically pure, e.g. crystalline, preparation, which is thermodynamically stable.
The objective of this invention was to synthesize a novel form of Nor-UDCA or Bis-Nor-UDCA at high quality, which has favourable purity, particle size characteristics and that is applicable for the treatment of cholestatic or metabolic liver diseases. The desired crystal form should be obtained in a consistent and reproducible manner by a scalable and industrial production process.
Since crystal modifications of a substance represent different crystal structures with potentially different properties, the main objective of the invention was to identify and select the thermodynamically stable polymorph/single crystalline form of Nor-UDCA that does not convert into another polymorphic form. This particular modification of Nor-UDCA should exhibit considerable chemical and physical advantages over metastable forms and should therefore be the substance of choice for further chemical and pharmaceutical development.
In addition, it is desirable to produce Nor-UDCA with a consistent particle size and morphology because the crystal habit affects important processing parameters such as flowability, bulk density and compressibility. Micronization of Nor-UDCA is preferred to increase the dissolution rate of the compound and by this the oral bioavailability.
The conditions of the purification and crystallisation process should produce the appropriate solid form of Nor-UDCA with reliable and reproducible polymorphic purity, chemical purity, crystal habit and yield. Micronization by milling in order to control the crystal size of Nor-UDCA can be avoided. Thereby, a common phenomenon upon micronization, namely amorphization, can be prevented.
The published method for the synthesis of Nor-UDCA is not suitable to meet pharmaceutical requirements. Especially the purification route is not effective to reach the desired product qualities with regard to polymorphic purity, chemical purity, crystal habit and yield. Conventional methods of purification do not allow to obtain a polymorph of Nor-UDCA or Bis-nor-UDCA having a very high chemical purity, e.g. such that the total amount of impurities is less than 0.05%. In addition, the known methods do not result in a particle size such that the D50 value is less than 10 μm without micronization. In addition, micronization would destroy the polymorphic purity of the product.